Amino acid N-carboxyanhydrides are used as intermediate raw materials for obtaining polypeptides from amino acids.
Generally known methods for synthesizing an amino acid N-carboxyanhydride are the method found by Leuchs in 1906 (Ber. Dtsch. Chem. Ges., 1906, 39, 857-859), the method proposed by Curtius et al. (J. Prakt. Chem., 1930, 125, 211-302), and the Fuchs-Farthing method (Nature (London), 1950, 165, 647; J. Chem. Soc., 1951, 3218-3222). Mainly used of these is the Fuchs-Farthing method, in which an amino acid N-carboxyanhydride is obtained in a high yield by the reaction of an amino acid with phosgene.
However, since phosgene is an exceedingly toxic gas, great care should be taken in handling this compound from the standpoints of environmental problem and safety. Use of phosgene is hence severely restricted and the industrial utilization of amino acid N-carboxyanhydrides is hence limited.
There are the following several investigations concerning techniques for synthesizing an amino acid N-carboxyanhydride without using phosgene.
(I) A method in which an amino acid N-carboxyanhydride is produced by reacting an amino acid with N,N-carbonyldiimidazole (patent document 1: U.S. Pat. No. 5,359,086).
(II) A method in which an amino acid N-carboxyanhydride is produced by reacting an N-carbamoylamino acid with an NO/O2 mixed gas (non-patent document 1: Tetrahedron Letters, 1996, 37, 9043).
(III) A method in which an amino acid N-carboxyanhydride is produced by reacting an amino acid with carbon dioxide in a supercritical state (patent document 2: JP-A-11-29560)
(IV) A method in which an amino acid N-carboxyanhydride is produced by reacting an aldehyde with carbon monoxide in the presence of a transition metal catalyst (patent document 3: JP-A-2000-327666).
(V) A method in which an amino acid N-carboxyanhydride is produced by reacting an amino acid with di-tert-butyl tricarbonate (patent document 4: JP-A-2002-322160; non-patent document 3: Macromolecules, 2004, 37, 251).
(VI) A method which comprises reacting N-nitrophenyl chloroformate with N-hydroxysuccinimide, reacting the resultant N-(4-nitrophenoxycarbonyloxy)succinimide with an amino acid to obtain an N-(4-nitrophenoxycarbonyl)amino acid, and synthesizing an amino acid amide from the N-(4-nitrophenoxycarbonyl)amino acid via an amino acid N-carboxyanhydride as an intermediate (non-patent document 2: Chemistry Letters, 2003, 32, 830).
However, those methods have the following drawbacks Method (I) is a case in which N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride was synthesized as an intermediate for an angiotension converting enzyme inhibitor by reacting N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine with N,N-carbonyldiimidazole There are unsolved problems concerning this method that the amino acid N-carboxyanhydride was not isolated and that N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine was the only amino acid actually used. Method (II) is industrially accompanied by a drawback because the target compound is produced via an exceedingly dangerous nitrosourea compound as an intermediate. Method (III) is not practical because it necessitates a large-scale apparatus for forming a supercritical state. Method (IV) has an unsolved problem that an optically active amino acid N-carboxyanhydride cannot be obtained. Method (V) has an unsolved problem concerning industrial use thereof because phosgene or triphosgene, which is toxic like phosgene, is presently used for synthesizing the di-tert-butyl tricarbonate. Method (VI) employs phosgene as a raw material for synthesizing the N-nitrophenyl chloroformate. Furthermore, the amino acid N-carboxyanhydride as an intermediate was not isolated.
As described above, those known methods have problems, for example, that a highly toxic raw material is used and an optically active amino acid N-carboxyanhydride cannot be obtained. There has been no known method for amino acid N-carboxyanhydride synthesis which is free from these problems.
Patent Document 1: U.S. Pat. No. 5,359,086
Non-Patent Document 1: Tetrahedron Letters, 1996, 371, 9043.
Patent Document 2: JP-A-11-29560
Patent Document 3: JP-A-2000-327666
Patent Document 4: JP-A-2002-322160
Non-Patent Document 2: Chemistry Letters, 2003, 32, 830.
Non-Patent Document 3: Macromolecules, 2004, 37, 2332.